With the advent of bicarbonate, in general sodium bicarbonate, being the preferred buffer and indeed natural buffer as compared to acetates or lactates, dialysis and replacement fluids preferably comprise bicarbonate. Dialysis and replacement fluids comprising bicarbonate anions in general need to be provided in the form of at least two separate component solutions, one comprising essentially only the bicarbonate component and the other comprising the so-called minor electrolytes including Ca++, Mg++ and K+ cations, and Na+. In some cases, a Na+-content, additional to that provided by NaHCO3, may conveniently be provided together with the bicarbonate component.
The need for separation of the bicarbonate component from other components which may comprise Ca++ and Mg++ cations is that the required amounts of these cations, in particular Ca++, cannot be stored together with bicarbonate for any appreciable period of time without precipitation of Ca++ and Mg++ carbonates. However, if the bicarbonate and Ca++ and Mg++ component solutions are mixed together shortly before use of the mixture as a dialysis or replacement fluid, precipitation does not occur within a time which is adequate for the mixture to be employed for its intended purpose.
One of the difficulties encountered with bicarbonate solutions i.e. in this case the bicarbonate component solution, is that such solutions are inclined to lose CO2 and form carbonates, which leads to an increased pH. There are suggestions, such as provided in U.S. Pat. No. 5,211,643, that it is of importance that the pH of bicarbonate solutions should be below 7.6 if formation of calcium carbonate seeds is to be avoided when mixing of the bicarbonate solution and Ca++-containing solution takes place, which in turn encourages further CaCO3 precipitation. On the other hand, there are alternative suggestions, as represented by PCT/US00/20486 (WO 01/17534 A1) that a low pH of less than 7.6 is not critical and indeed a pH of 8.6 to 10 is indicated to be an acceptable pH range for the bicarbonate solution. In this PCT publication, it is furthermore indicated that the need, for a gas-impermeable over-wrap limiting migration or escape of CO2 from the bicarbonate solution can be dispensed with. In other words, no harm is seen in allowing CO2 to escape from the bicarbonate solution and for the attendant pH to increase to a value of from 8.6 up to even 10, suggesting a higher concentration of CO3−− ions.
The present invention is concerned with advantageous alternatives to both of the approaches discussed above. Thus, in the case of U.S. Pat. No. 5,211,643, the need for the bicarbonate solution to be possessed of a pH below 7.6 is critical to the invention there described. Products involving sodium bicarbonate solutions having a pH in excess of 7.6, for example 7.8 or even up to 8.8, however, have not demonstrated difficulties arising from calcium carbonate precipitation when mixed with Ca++-containing solutions, provided that the mixtures are employed for their intended purpose within a reasonable period of time, such as within 24 hours from the time that the component solutions are mixed. On the other hand, it is known that bicarbonate-containing solutions contained in flexible plastic material bags are inclined to lose CO2 and for the pH of the solution to thereby reach higher pH values. More particularly, it is of importance that the final mixture of the alkaline bicarbonate solution with the Ca++-containing solution which is generally an acid solution, usually comprising both Ca++ and Mg++ cations, be within a physiologically acceptable pH range of about 7.2 to 7.3. It is accordingly of importance to gain proper control over the extent of CO2 migration from bicarbonate solutions. One mode of gaining some control involves use of gas-impermeable over-wrap material over-wrapping flexible plastic bags each separately containing the components of the desired mixture of bicarbonate and acid solutions. One practical difficulty with this procedure is that the over-wrap material, also in the form of a flexible bag, is normally evacuated of air so that the over-wrap material seats over the surfaces of plastic material containing the bicarbonate and other solutions. This evacuation procedure inevitably leads to creases in the over-wrap material forming pockets into which CO2 gas may escape through the plastic material container from the bicarbonate solution. Since the volume occupied by the over-wrap material is necessarily greater than the volume of the flexible bag containers containing the bicarbonate and other solutions, there is always a volume within the over-wrap material which can receive CO2 gas escaping from the bicarbonate solution.
Escape of carbon dioxide from the sodium bicarbonate component solution may be limited by means of gas-impermeable over-wrap film material enclosing the flexible bag assembly. Over-wrap film materials having gas-impermeable characteristics include polypropylene-polyvinyl alcohol copolymers which however need to be employed in their over-wrap role subsequent to sterilization of the filled flexible bag assembly if the gas-impermeable characteristics thereof are to be retained.
Film materials employed for producing the multi-compartment flexible bag assembly might be of PVC or non-PVC type. Such materials as are presently available are however invariably permeable to carbon dioxide gas to varying degrees. Such permeation of carbon dioxide from the sodium bicarbonate component solution leads to an increase in sodium carbonate content and hence to increased pH levels. Furthermore, loss of carbon dioxide leads to a lowering of the desired content or availability of bicarbonate ions in the final admixed composition of the sodium bicarbonate component solution and the acid component solution. The escape of carbon dioxide is thus to be avoided or controlled as best as is possible.
The present invention is more particularly directed to achieving improved control and limitation of the amounts of CO2 gas which can escape from bicarbonate-containing solutions into gas-impermeable over-wrap material enclosing bicarbonate-containing and other solutions. The improved control and limitation of the amounts of CO2 gas which can escape or does escape from bicarbonate-containing solutions may also provide opportunities for eliminating the need for an over-wrap. An additional associated consideration is related to influences on one another of partial pressures of CO2 of different solutions to be mixed together to obtain final peritoneal dislysis, hemodialysis and replacement fluids. The invention accordingly involves evaluations of the partial pressure of CO2 of bicarbonate-containing solutions and other solutions with which the bicarbonate-containing solutions are to be mixed.